Toltrazuril, (1-methyl-3-[3-methyl-4-[4-(trifluoromethylthio)phenoxy]-phenyl]-1,3,5-triazin-2,4,6(1H,3H,5H)-trione) of formula (I), is an agent widely used in the veterinary field for the prevention and treatment of coccidiosis, particularly in poultry and pigs.

The preparation of toltrazuril is reported in U.S. Pat. No. 3,966,725 and U.S. Pat. No. 4,219,552, which describe a general process for the preparation of various 1-(4-phenoxyphenyl)-1,3,5-triazin-2,4,6 1H,3H,5H)-triones. In the case of toltrazuril, the process involves reacting 1-[3-methyl-4-[4 (trifluoromethylthio)phenoxy]phenyl]-3-methylurea of formula (II) with chlorocarbonyl isocyanate, as reported in Scheme 1.

U.S. Pat. No. 4,874,860 and DE 4239000 disclose the preparation of toltrazuril by cyclisation of N-methyl-N′-[3-methyl-4-[4-[(trifluoromethyl)thio]phenoxy]-phenyl]imidodicarbonic diamide of formula (III), commonly known as biuret toltrazuril intermediate, with diethyl carbonate in the presence of sodium methylate, as reported in Scheme 2.

The biuret intermediate (III) is obtained in turn by reacting the aniline intermediate 3-methyl-4-[4-(trifluoromethylthio)phenoxy]benzenamine (IV) with phosgene to give the corresponding isocyanate (V), which is then reacted with N-methylurea, as reported in Scheme 3.

CN 101265236 discloses the reaction of isocyanate (V) with intermediate (IV) and triphosgene instead of phosgene, while CN102108067 describes the reaction between intermediate (IV) and BOC-anhydride/DMAP.
CN 101108831 describes the preparation of toltrazuril wherein the ureide intermediate (II) is obtained by treating aniline (IV) with triphosgene to give isocyanate (V), which is then reacted with methylamine, as reported in Scheme 4.

CN 102731351 discloses the reaction of aniline (IV) with KCNO giving urea (VI), which is converted to biuret (III) by reaction with methylaminoformyl chloride, as depicted in Scheme 5.

The synthesis routes of toltrazuril via intermediate (III) reported so far therefore involve the use of potentially hazardous reagents like phosgene and triphosgene and/or a step involving unstable intermediates like isocyanates.